{
  "abstract": "Introduction Despite the identification of multiple susceptibility loci by genome-wide association studies (GWAS), considerable chronic obstructive pulmonary disease (COPD) heritability remains unexplained.Aim To identify interaction networks of airway epithelial cell DNA methylation in COPD and further explore potential correlations with airway bacterial composition, as potentially collective regulators of biological pathways influencing COPD severity.Methods Using DNA isolated from bronchial airway brushings of 67 ever-smokers (>20 pack-years) from the SubPopulations and InteRmediate Outcomes Measures in COPD Study (SPIROMICS), we assessed proportion of DNA methylation (β) by epigenome-wide association study (EWAS) and examined associations of differentially methylated CpG probes (DMPs) with risk for moderate-to-severe COPD (N=34) versus absent or mild COPD (N=33). We tested co-methylation modules generated by Weighted Correlation Network Analyses (WGCNA) for associations with moderate-to-severe COPD and with bacterial genus-level relative abundances (16S rRNA sequencing).Results EWAS-identified nominally significant DMPs enriched for lung function GWAS loci. Eigengenes in six WGCNA modules were associated with moderate-to-severe COPD (false discovery rate <0.05). Four of those modules were enriched for forced expiratory volume in 1 s/forced vital capacity GWAS loci, and five overlapped with DMPs from EWAS. Overlapping CpG loci in three COPD-associated modules were adjacent to mucin genes; one had 10 genes highly ranked by connectivity with MUC5B, including important pathway genes: B3GNT6, DGKI and ITGA8. CpGs in an independent COPD-associated module showed the most correlations with Rothia, with directionality suggestive of negative associations with moderate-severe COPD.Conclusions Bronchial epithelial DNA methylation modules enriched for lung function GWAS loci associate with COPD severity in SPIROMICS. Potential module relationships to bronchial bacterial composition require further validation.",
  "authors": [
    {
      "affiliations": [
        "Mayo Clinic Arizona, Scottsdale, Arizona, USA"
      ],
      "name": "Shuo Cao"
    },
    {
      "affiliations": [
        "Mayo Clinic, Scottsdale, Arizona, USA"
      ],
      "name": "Abhishek Shrivastav"
    },
    {
      "affiliations": [
        "Mayo Clinic, Scottsdale, Arizona, USA"
      ],
      "name": "Eugene R Bleecker"
    },
    {
      "affiliations": [
        "University of Michigan, Ann Arbor, Michigan, USA"
      ],
      "name": "Siddharth Madapoosi"
    },
    {
      "affiliations": [
        "University of Michigan, Ann Arbor, Michigan, USA"
      ],
      "name": "John Erb-Downward"
    },
    {
      "affiliations": [
        "Mayo Clinic, Scottsdale, Arizona, USA"
      ],
      "name": "Joe Zein"
    },
    {
      "affiliations": [
        "Mayo Clinic, Scottsdale, Arizona, USA"
      ],
      "name": "Xianfeng Chen"
    },
    {
      "affiliations": [
        "Wake Forest School of Medicine, Winston-Salem, North Carolina, USA"
      ],
      "name": "Timothy D Howard"
    },
    {
      "affiliations": [
        "Wake Forest School of Medicine, Winston-Salem, North Carolina, USA"
      ],
      "name": "Gregory A Hawkins"
    },
    {
      "affiliations": [
        "University of California Los Angeles, Los Angeles, California, USA"
      ],
      "name": "Igor Z Barjaktarevic"
    },
    {
      "affiliations": [
        "Cleveland Clinic, Cleveland, Ohio, USA"
      ],
      "name": "Russell Bowler"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, New York, USA"
      ],
      "name": "Robert Graham Barr"
    },
    {
      "affiliations": [
        "Internal Medicine, University of Iowa, Iowa, Iowa, USA"
      ],
      "name": "Alejandro Comellas"
    },
    {
      "affiliations": [
        "University of California Los Angeles, Los Angeles, California, USA"
      ],
      "name": "Christopher B Cooper"
    },
    {
      "affiliations": [
        "Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA"
      ],
      "name": "David Couper"
    },
    {
      "affiliations": [
        "Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA"
      ],
      "name": "Meilan Han"
    },
    {
      "affiliations": [
        "Medicine, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Nadia N Hansel"
    },
    {
      "affiliations": [
        "Center for Genomics and Personalized Medicine Research, Wake Forest Health Sciences, Winston Salem, North Carolina, USA"
      ],
      "name": "Annette T Hastie"
    },
    {
      "affiliations": [
        "Institute of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA"
      ],
      "name": "Robert Kaner"
    },
    {
      "affiliations": [
        "Medicine, University of Utah, Salt Lake City, Utah, USA"
      ],
      "name": "Richard E Kanner"
    },
    {
      "affiliations": [
        "Division of Pulmonary and Critical Care Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Victor Kim"
    },
    {
      "affiliations": [
        "University of Massachusetts, Worcester, Massachusetts, USA"
      ],
      "name": "Fernando J Martinez"
    },
    {
      "affiliations": [
        "Center for Genomics and Personalized Medicine Research, Wake Forest Health Sciences, Winston Salem, North Carolina, USA"
      ],
      "name": "Wendy C Moore"
    },
    {
      "affiliations": [
        "Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina, USA"
      ],
      "name": "Wanda K O’Neal"
    },
    {
      "affiliations": [
        "Internal Medicine/Pulmonary and Critical Care, University of Utah, Salt Lake City, Utah, USA"
      ],
      "name": "Robert Paine"
    },
    {
      "affiliations": [
        "Department of Medicine, Columbia University, New York, New York, USA"
      ],
      "name": "Benjamin Smith"
    },
    {
      "affiliations": [
        "Radiology, University of Iowa, Iowa City, Iowa, USA"
      ],
      "name": "Eric A Hoffman"
    },
    {
      "affiliations": [
        "Mayo Clinic, Scottsdale, Arizona, USA"
      ],
      "name": "Deborah A Meyers"
    },
    {
      "affiliations": [
        "University of California San Francisco, San Francisco, California, USA"
      ],
      "name": "Prescott G Woodruff"
    },
    {
      "affiliations": [
        "Medicine, University of California San Francisco, San Francisco, California, USA"
      ],
      "name": "Stephanie Christenson"
    },
    {
      "affiliations": [
        "Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA"
      ],
      "name": "Jeffrey L Curtis"
    },
    {
      "affiliations": [
        "University of Michigan, Ann Arbor, Michigan, USA"
      ],
      "name": "Yvonne Jean Huang"
    },
    {
      "affiliations": [
        "Mayo Clinic, Scottsdale, Arizona, USA"
      ],
      "name": "Victor E Ortega"
    }
  ],
  "title": "Epigenomic study of the lower airway reveals COPD-associated methylation patterns and potential microbiota links",
  "uid": "ae8fc598-8c38-5c88-b3d2-87c6af690358"
}